In most manipulations, we use our fingertips to apply time-varying forces to the target object in controlled directions. Here we used microneurography to assess how single tactile afferents encode the direction of fingertip forces at magnitudes, rates, and directions comparable to those arising in everyday manipulations. Using a flat stimulus surface, we applied forces to a standard site on the fingertip while recording impulse activity in 196 tactile afferents with receptive fields distributed over the entire terminal phalanx. Forces were applied in one of five directions: normal force and forces at a 20 degrees angle from the normal in the radial, distal, ulnar, or proximal directions. Nearly all afferents responded, and the responses in most slowly adapting (SA)-I, SA-II, and fast adapting (FA)-I afferents were broadly tuned to a preferred direction of force. Among afferents of each type, the preferred directions were distributed in all angular directions with reference to the stimulation site, but not uniformly. The SA-I population was biased for tangential force components in the distal direction, the SA-II population was biased in the proximal direction, and the FA-I population was biased in the proximal and radial directions. Anisotropic mechanical properties of the fingertip and the spatial relationship between the receptive field center of the afferent and the stimulus site appeared to influence the preferred direction in a manner dependent on afferent type. We conclude that tactile afferents from the whole terminal phalanx potentially contribute to the encoding of direction of fingertip forces similar to those that occur when subjects manipulate objects under natural conditions.

3.

Birznieks, Ingvars

et al.

Prince of Wales Medical Research Institute, Sydney, New South Wales 2031, Australia.

Macefield, Vaughan G

Prince of Wales Medical Research Institute, Sydney, New South Wales 2031, Australia.

There are clusters of slowly adapting (SA) mechanoreceptors in the skin folds bordering the nail. These "SA-IInail" afferents, which constitute nearly one fifth of the tactile afferents innervating the fingertip, possess the general discharge characteristics of slowly adapting type II (SA-II) tactile afferents located elsewhere in the glabrous skin of the human hand. Little is known about the signals in the SA-IInail afferents when the fingertips interact with objects. Here we show that SA-IInail afferents reliably respond to fingertip forces comparable to those arising in everyday manipulations. Using a flat stimulus surface, we applied forces to the finger pad while recording impulse activity in 17 SA-IInail afferents. Ramp-and-hold forces (amplitude 4 N, rate 10 N/s) were applied normal to the skin, and at 10, 20, or 30 degrees from the normal in eight radial directions with reference to the primary site of contact (25 force directions in total). All afferents responded to the force stimuli, and the responsiveness of all but one afferents was broadly tuned to a preferred direction of force. The preferred directions among afferents were distributed all around the angular space, suggesting that the population of SA-IInail afferents could encode force direction. We conclude that signals in the population of SA-IInail afferents terminating in the nail walls contain vectorial information about fingertip forces. The particular tactile features of contacted surfaces would less influence force-related signals in SA-IInail afferents than force-related signals present in afferents terminating in the volar skin areas that directly contact objects.

The neurotrophic factors of the nerve growth factor family (neurotrophins) have been shown to promote neuronal survival after brain injury and in various models of neurodegenerative conditions. However, it has not been determined whether neurotrophin treatment results in the maintenance of function of the rescued cells. Here we have used the retrograde degeneration of geniculate neurons as a model system to evaluate neuronal rescue and sparing of function after administration of brain-derived neurotrophic factor (BDNF). Death of geniculate neurons was induced by a visual cortex lesion in adult rats, and exogenous BDNF was delivered to the axotomized geniculate cells via anterograde transport after injection into the eye. By microelectrode recordings from the geniculate in vivo we have measured several physiological parameters such as contrast threshold, spatial resolution (visual acuity), signal-to-noise ratio, temporal resolution, and response latency. In control lesioned animals we found that geniculate cell dysfunction precedes the onset of neuronal death, indicating that an assessment of neuronal number per se is not predictive of functional performance. The administration of BDNF resulted in a highly significant cell-saving effect up to 2 weeks after the cortical damage and maintained nearly normal physiological responses in the geniculate. This preservation of function in adult axotomized neurons suggests possible therapeutic applications of BDNF.

Observations of knock-out mice suggest that breathing at birth requires correct development of a specific hindbrain territory corresponding to rhombomeres (r) 3 and 4. Focusing on this territory, we examined the development of a neuronal rhythm generator in the chick embryo. We show that rhythmic activity in r4 is inducible after developmental stage 10 through interaction with r3. Although the nature of this interaction remains obscure, we find that the expression of Krox20, a segmentation gene responsible for specifying r3 and r5, is sufficient to endow other rhombomeres with the capacity to induce rhythmic activity in r4. Induction is robust, because it can be reproduced with r2 and r6 instead of r4 and with any hindbrain territory that normally expresses Krox20 (r3, r5) or can be forced to do so (r1, r4). Interestingly, the interaction between r4 and r3/r5 that results in rhythm production can only take place through the anterior border of r4, revealing a heretofore unsuspected polarity in individual rhombomeres. The r4 rhythm generator appears to be homologous to a murine respiratory parafacial neuronal system developing in r4 under the control of Krox20 and Hoxa1. These results identify a late role for Krox20 at the onset of neurogenesis.

Numerous studies have shown that people are adept at learning novel object dynamics, linking applied force and motion, when performing reaching movements with hand-held objects. Here we investigated whether the control of rapid corrective arm responses, elicited in response to visual perturbations, has access to such newly acquired knowledge of object dynamics. Participants first learned to make reaching movements while grasping an object subjected to complex load forces that depended on the distance and angle of the hand from the start position. During a subsequent test phase, we examined grip and load force coordination during corrective arm movements elicited (within similar to 150 ms) in response to viewed sudden lateral shifts (1.5 cm) in target or object position. We hypothesized that, if knowledge of object dynamics is incorporated in the control of the corrective responses, grip force changes would anticipate the unusual load force changes associated with the corrective arm movements so as to support grasp stability. Indeed, we found that the participants generated grip force adjustments tightly coupled, both spatially and temporally, to the load force changes associated with the arm movement corrections. We submit that recently learned novel object dynamics are effectively integrated into sensorimotor control policies that support rapid visually driven arm corrective actions during transport of hand held objects.

Muscle spindles are commonly considered as stretch receptors encoding movement, but the functional consequence of their efferent control has remained unclear. The "alpha-gamma coactivation" hypothesis states that activity in a muscle is positively related to the output of its spindle afferents. However, in addition to the above, possible reciprocal inhibition of spindle controllers entails a negative relationship between contractile activity in one muscle and spindle afferent output from its antagonist. By recording spindle afferent responses from alert humans using microneurography, I show that spindle output does reflect antagonistic muscle balance. Specifically, regardless of identical kinematic profiles across active finger movements, stretch of the loaded antagonist muscle (i.e., extensor) was accompanied by increased afferent firing rates from this muscle compared with the baseline case of no constant external load. In contrast, spindle firing rates from the stretching antagonist were lowest when the agonist muscle powering movement (i.e., flexor) acted against an additional resistive load. Stepwise regressions confirmed that instantaneous velocity, extensor, and flexor muscle activity had a significant effect on spindle afferent responses, with flexor activity having a negative effect. Therefore, the results indicate that, as consequence of their efferent control, spindle sensitivity (gain) to muscle stretch reflects the balance of activity between antagonistic muscles rather than only the activity of the spindle-bearing muscle.

The response of 70 cutaneous, low-threshold mechanoreceptors in the human median, radial and inferior alveolar nerves to well controlled brush stimuli moving across the receptive field was quantitatively studied. Microneurography was used to obtain the response of each to multiple velocities from 0.5 to 32 cm/sec in at least two opposing directions. A high degree of response consistency was observed from the slowly adapting receptors to replication of the same stimulus and to a lesser, but significant degree from the fast adapting receptors. The evoked discharge reflected up to three partially overlapping phases of the moving stimulus: skin compression, indentation, and stretch. Although the overall discharge rate increased with both stimulus velocity and force, the spatial discharge pattern was preserved to a high degrees. In contrast, the discharge patterns differed for opposing and orthogonal directions. Reducing the area of skin surrounding the receptive field that was contacted by the moving stimuli had little effect on the evoked response. Individual mechanoreceptors display highly reliable differences to brush stimuli moving at different velocities. to brush stimuli moving at different velocities. Moreover, different directions of movement evoke differences in the discharge that are consistently observed upon replication of the same stimuli. Despite the richness and consistency in the spatial discharge pattern displayed by individual receptors, it is argued that the details of the patterns are not likely used by the CNS to infer information about direction and velocity of movement across the skin. Rather, the intensity of discharge is proposed as a plausible information-bearing attribute of the stimulus-evoked response.

The mean firing rate evoked in 70 cutaneous, low-threshold mechanoreceptors in the human median, radial, and inferior alveolar nerves by stimulus motion across the skin was quantitatively studied. Moving stimuli, controlled for velocity, direction, and length of skin traversed, were provided by a servo-controlled motor that carried a brush across the receptive field. Each unit was studied with stimuli delivered at multiple velocities from 0.5 to 32 cm/sec in at least two opposing directions. A power function provided an excellent description of the MFR-versus-velocity relationship. The exponent n was interpreted to reflect the receptor's sensitivity to changes in stimulus velocity, and the multiplicative constant c, the predicted response to stimuli moving at 1.0 cm/sec. The fast adapting mechanoreceptors exhibited higher sensitivity to stimulus velocity than the slowly adapting mechanoreceptors. The mean velocity at which the fast adapting units were predicted to first respond to movement was also higher. Estimates of n, c, or both differed significantly for stimuli delivered in opposing directions for more than 70% of the mechanoreceptors. No direction of motion consistently led to power function parameters with higher values so as to suggest a "preferred" regional direction of motion for the entire population. Neither the directional difference in n nor c could be attributed to directional differences in the forces applied across the receptive fields. These findings suggest that information about velocity and direction is represented in the mean firing rate responses evoked in the population of mechanoreceptors activated by a moving tactile stimulus.

To investigate the role of sex steroids in sex differences in the response of rats to the potent inflammatory mediator bradykinin (BK), we evaluated the effect of sex steroid manipulation on the magnitude of BK-induced synovial plasma extravasation (PE). The magnitude of BK-induced PE is markedly less in females. Ovariectomy of female rats increased BK-induced PE, and administration of 17 beta-estradiol to ovariectomized female rats reconstituted the female phenotype. Castration in male rats decreased BK-induced PE, and administration of testosterone or its nonmetabolizable analog dihydrotestosterone reconstituted the male phenotype. The results of these experiments strongly support the role of both male and female sex steroids in sex differences in the inflammatory response. Because the stress axes are sexually dimorphic and are important in the regulation of the inflammatory response, we evaluated the contribution of the hypothalamic-pituitary-adrenal and the sympathoadrenal axes to sex differences in BK-induced PE. Neither hypophysectomy nor inhibition of corticosteroid synthesis affected BK-induced PE in female or male rats. Adrenal denervation in females produced the same magnitude increase in BK-induced PE as adrenalectomy or ovariectomy, suggesting that the adrenal medullary factor(s) in females may account for the female sex steroid effect on BK-induced PE. Furthermore, we have demonstrated that in female but not male rats, estrogen receptor a! immunoreactivity is present on medullary but not cortical cells in the adrenal gland. These data suggest that regulation of the inflammatory response by female sex steroids is strongly dependent on the sympathoadrenal axis, possibly by its action on estrogen receptors on adrenal medullary cells.

To determine whether other digits move when normal humans attempt to move just one digit, we asked 10 right-handed subjects to move one finger at a time while we recorded the motion of all five digits simultaneously with both a video motion analysis system and an instrumented glove. We quantified the independence of the digits to compare (1) the different digits, (2) the right versus the left hand, and (3) movements at a self-paced frequency versus externally paced movements at 3 Hz. We also quantified the degree to which motion occurred at the proximal, middle, or distal joint of each digit. Even when asked to move just one finger, normal human subjects produced motion in other digits. Movements of the thumb, index finger, and little finger typically were more highly individuated than were movements of the middle or ring fingers. Fingers of the dominant hand were not more independent than were those of the nondominant hand. Self-paced movements made at approximately 2 Hz were more highly individuated than were externally paced movements at 3 Hz. Angular motion tended to be greatest at the middle joint of each digit, with increased angular motion at the proximal and distal joints during 3 Hz movements. Simultaneous motion of noninstructed digits may result in part from passive mechanical connections between the digits, in part from the organization of multitendoned finger muscles, and in part from distributed neural control of the hand.

A central concept in neuroscience is that the CNS signals the sensory discrepancy between the predicted and actual sensory consequences of action. It has been proposed that the cerebellum and parietal cortex are involved in this process. A discrepancy will trigger preprogrammed corrective responses and update the engaged sensorimotor memories. Here we use functional magnetic resonance imaging with an event-related design to investigate the neuronal correlates of such discrepancies. Healthy adults repeatedly lifted an object between their right index fingers and thumbs, and on some lifting trials, the weight of the object was unpredictably changed between light (230 g) and heavy (830 g). Regardless of whether the weight was heavier or lighter than predicted, activity was found in the right inferior parietal cortex (supramarginal gyrus). This suggests that this region is involved in the comparison of the predicted and actual sensory input and the updating of the sensorimotor memories. When the object was lighter or heavier than predicted, two different types of preprogrammed force corrections occurred. There was a slow force increase when the weight of the object was heavier than predicted. This corrective response was associated with activity in the left primary motor and somatosensory cortices. The fast termination of the excessive force when the object was lighter than predicted activated the right cerebellum. These findings show how the parietal cortex, cerebellum, and motor cortex are involved in the signaling of the discrepancy between predicated and actual sensory feedback and the associated corrective mechanisms.

The general view is that both glycine (Eccles, 1964) and GABA (Curtis and Felix, 1971) evoke postsynaptic inhibition in spinal motor neurons. In newborn or juvenile animals, there are conflicting results showing postsynaptic inhibition in motor neurons by corelease of GABA and glycine (Jonas et al., 1998) or by glycine alone (Bhumbra et al., 2012). To resolve the relative contributions of GABA and glycine to postsynaptic inhibition, we performed in vivo intracellular recordings from forelimb motor neurons in adult mice. Postsynaptic potentials evoked from segmental, propriospinal, and bulbospinal systems in motor neurons were compared across four different conditions: control, after gabazine, gabazine followed by strychnine, and strychnine alone. No significant differences were observed in the proportion of IPSPs and EPSPs between control and gabazine conditions. In contrast, EPSPs but not IPSPs were recorded after adding strychnine with gabazine or administering strychnine alone, suggesting an exclusive role for glycine in postsynaptic inhibition. To test whether the injected (intraperitoneal) dose of gabazine blocked GABAergic inhibitory transmission, we evoked GABA(A) receptor-mediated monosynaptic IPSPs in deep cerebellar nuclei neurons by stimulation of Purkinje cell fibers. No monosynaptic IPSPs could be recorded in the presence of gabazine, showing the efficacy of gabazine treatment. Our results demonstrate that, in the intact adult mouse, the postsynaptic inhibitory effects in spinal motor neurons exerted by three different systems, intrasegmental and intersegmental as well as supraspinal, are exclusively glycinergic. These findings emphasize the importance of glycinergic postsynaptic inhibition in motor neurons and challenge the view that GABA also contributes.

We analyzed the coordination between gaze behavior, fingertip movements, and movements of the manipulated object when subjects reached for and grasped a bar and moved it to press a target-switch. Subjects almost exclusively fixated certain landmarks critical for the control of the task. Landmarks at which contact events took place were obligatory gaze targets. These included the grasp site on the bar, the target, and the support surface where the bar was returned after target contact. Any obstacle in the direct movement path and the tip of the bar were optional landmarks. Subjects never fixated the hand or the moving bar. Gaze and hand/bar movements were linked concerning landmarks, with gaze leading. The instant that gaze exited a given landmark coincided with a kinematic event at that landmark in a manner suggesting that subjects monitored critical kinematic events for phasic verification of task progress and subgoal completion. For both the obstacle and target, subjects directed saccades and fixations to sites that were offset from the physical extension of the objects. Fixations related to an obstacle appeared to specify a location around which the extending tip of the bar should travel. We conclude that gaze supports hand movement planning by marking key positions to which the fingertips or grasped object are subsequently directed. The salience of gaze targets arises from the functional sensorimotor requirements of the task. We further suggest that gaze control contributes to the development and maintenance of sensorimotor correlation matrices that support predictive motor control in manipulation.

Encoding and retrieval processes enhance long-term memory performance. The efficiency of encoding processes has recently been linked to representational consistency: the reactivation of a representation that gets more specific each time an item is further studied. Here we examined the complementary hypothesis of whether the efficiency of retrieval processes also is linked to representational consistency. Alternatively, recurrent retrieval might foster representational variability—the altering or adding of underlying memory representa- tions. Human participants studied 60 Swahili–Swedish word pairs before being scanned with fMRI the same day and 1 week later. On Day 1, participants were tested three times on each word pair, and on Day 7 each pair was tested once. A BOLD signal change in right superior parietal cortex was associated with subsequent memory on Day 1 and with successful long-term retention on Day 7. A representational similarity analysis in this parietal region revealed that beneficial recurrent retrieval was associated with representational variability, such that the pattern similarity on Day 1 was lower for retrieved words subsequently remembered compared with those subsequently forgot- ten. This was mirrored by a monotonically decreased BOLD signal change in dorsolateral prefrontal cortex on Day 1 as a function of repeated successful retrieval for words subsequently remembered, but not for words subsequently forgotten. This reduction in prefrontal response could reflect reduced demands on cognitive control. Collectively, the results offer novel insights into why memory retention benefits from repeated retrieval, and they suggest fundamental differences between repeated study and repeated testing.

Several studies have linked the KIBRA rs17070145 T polymorphism to superior episodic memory in healthy humans. One study investigated the effect of KIBRA on brain activation patterns (Papassotiropoulos et al., 2006) and observed increased hippocampal activation in noncarriers of the T allele during retrieval. Noncarriers were interpreted to need more hippocampal activation to reach the same performance level as T carriers. Using large behavioral (N = 2230) and fMRI (N = 83) samples, we replicated the KIBRA effect on episodic memory performance, but found increased hippocampal activation in T carriers during episodic retrieval. There was no evidence of compensatory brain activation in noncarriers within the hippocampal region. In the main fMRI sample, T carriers performed better than noncarriers during scanning but, importantly, the difference in hippocampus activation remained after post hoc matching according to performance, sex, and age (N = 64). These findings link enhanced memory performance in KIBRA T allele carriers to elevated hippocampal functioning, rather than to neural compensation in noncarriers.

Midbrain dopamine neuron dysfunction contributes to various psychiatric and neurological diseases, including drug addiction and Parkinson's disease. Because of its well established dopaminotrophic effects, the therapeutic potential of glial cell line-derived neurotrophic factor (GDNF) has been studied extensively in various disorders with disturbed dopamine homeostasis. However, the outcomes from preclinical and clinical studies vary, highlighting a need for a better understanding of the physiological role of GDNF on striatal dopaminergic function. Nevertheless, the current lack of appropriate animal models has limited this understanding. Therefore, we have generated novel mouse models to study conditional Gdnf deletion in the CNS during embryonic development and reduction of striatal GDNF levels in adult mice via AAV-Cre delivery. We found that both of these mice have reduced amphetamine-induced locomotor response and striatal dopamine efflux. Embryonic GDNF deletion in the CNS did not affect striatal dopamine levels or dopamine release, but dopamine reuptake was increased due to increased levels of both total and synaptic membrane-associated dopamine transporters. Collectively, these results suggest that endogenous GDNF plays an important role in regulating the function of dopamine transporters in the striatum.

Stimulus-dependent expression of the retinoic acid-inactivating enzyme Cyp26B1 in olfactory sensory neurons (OSNs) forms a dorsomedial (DM)-ventrolateral (VL) gradient in the mouse olfactory epithelium. The gradient correlates spatially with different rates of OSN turnover, as well as the functional organization of the olfactory sensory map, into overlapping zones of OSNs that express different odorant receptors (ORs). Here, we analyze transgenic mice that, instead of a stimulus-dependent Cyp26B1 gradient, have constitutive Cyp26B1 levels in all OSNs. Starting postnatally, OSN differentiation is decreased and progenitor proliferation is increased. Initially, these effects are selective to the VL-most zone and correlate with reduced ATF5 expression and accumulation of OSNs that do not express ORs. Transcription factor ATF5 is known to stabilize OR gene choice via onset of the stimulus-transducing enzyme adenylyl cyclase type 3. During further postnatal development of Cyp26B1 mice, an anomalous DMhigh-VLlow expression gradient of adenylyl cyclase type 3 appears, which coincides with altered OR frequencies and OR zones. All OR zones expand ventrolaterally except for the VL-most zone, which contracts. The expansion results in an increased zonal overlap that is also evident in the innervation pattern of OSN axon terminals in olfactory bulbs. These findings together identify a mechanism by which postnatal sensory-stimulated vitamin A metabolism modifies the generation of spatially specified neurons and their precise topographic connectivity. The distributed patterns of vitamin A-metabolizing enzymes in the nervous system suggest the possibility that the mechanism may also regulate neuroplasticity in circuits other than the olfactory sensory map.

Intraindividual variability (IIV) reflects within-person changes in performance, such as trial-by-trial fluctuations on a reaction-time (RT) task. The neural underpinnings of IIV remain largely unknown. The neurotransmitter dopamine (DA) is of particular interest here, as human populations that exhibit DA alterations, such as the elderly, attention deficit hyperactivity disorder children, persons with schizophrenia, and Parkinson patients, also show increased behavioral IIV. We examined links between DA D-1 binding potential (BP) in multiple brain regions and IIV for the control and interference conditions of the Multi-Source Interference Task (MSIT), tapping the cingulo-fronto-parietal attention network. Participants were 18 young and 20 healthy old adults. PET and the radioligand [C-11]SCH23390 were used to determine D-1 BP. The intraindividual standard deviation (ISD) was computed across successful latency trials of the MSIT conditions, independent of mean RT differences due to age, trial, and condition. Increasing ISDs were associated with increasing age and diminished D-1 binding in several brain regions (anterior cingulate gyrus, dorsolateral prefrontal cortex, and parietal cortex) for the interference, but not control, condition. Analyses of partial associations indicate that the association between age and IIV in the interference condition was linked to D-1 receptor losses in task-relevant brain regions. These findings suggest that dysfunctional DA modulation may contribute to increased variability in cognitive performance among older adults.

The assembly of neural circuits is dependent upon the generation of specific neuronal subtypes, each subtype displaying unique properties that direct the formation of selective connections with appropriate target cells. Actions of transcription factors in neural progenitors and postmitotic cells are key regulators in this process. LIM-homeodomain transcription factors control crucial aspects of neuronal differentiation, including subtype identity and axon guidance. Nonetheless, their regulation during development is poorly understood and the identity of the downstream molecular effectors of their activity remains largely unknown. Here, we demonstrate that the Lhx2 transcription factor is dynamically regulated in distinct pools of thalamic neurons during the development of thalamocortical connectivity in mice. Indeed, overexpression of Lhx2 provokes defective thalamocortical axon guidance in vivo, while specific conditional deletion of Lhx2 in the thalamus produces topographic defects that alter projections from the medial geniculate nucleus and from the caudal ventrobasal nucleus in particular. Moreover, we demonstrate that Lhx2 influences axon guidance and the topographical sorting of axons by regulating the expression of Robo1 and Robo2 guidance receptors, which are essential for these axons to establish correct connections in the cerebral cortex. Finally, augmenting Robo1 function restores normal axon guidance in Lhx2-overexpressing neurons. By regulating axon guidance receptors, such as Robo1 and Robo2, Lhx2 differentially regulates the axon guidance program of distinct populations of thalamic neurons, thus enabling the establishment of specific neural connections.

Tauopathies are neurodegenerative diseases characterized by intraneuronal inclusions of hyperphosphorylated tau protein and abnormal expression of brain-derived neurotrophic factor (BDNF), a key modulator of neuronal survival and function. The severity of both these pathological hallmarks correlate with the degree of cognitive impairment in patients. However, how tau pathology specifically modifies BDNF signaling and affects neuronal function during early prodromal stages of tauopathy remains unclear. Here, we report that the mild tauopathy developing in retinal ganglion cells (RGCs) of the P301S tau transgenic (P301S) mouse induces functional retinal changes by disrupting BDNF signaling via the TrkB receptor. In adult P301S mice, the physiological visual response of RGCs to pattern light stimuli and retinal acuity decline significantly. As a consequence, the activity-dependent secretion of BDNF in the vitreous is impaired in P301S mice. Further, in P301S retinas, TrkB receptors are selectively upregulated, but uncoupled from downstream extracellular signal-regulated kinase (ERK) 1/2 signaling. We also show that the impairment of TrkB signaling is triggered by tau pathology and mediates the tau-induced dysfunction of visual response. Overall our results identify a neurotrophin-mediated mechanism by which tau induces neuronal dysfunction during prodromal stages of tauopathy and define tau-driven pathophysiological changes of potential value to support early diagnosis and informed therapeutic decisions.

Connectivity and dendritic properties are determinants of plasticity that are layer and cell-type specific in the neocortex. However, the impact of experience-dependent plasticity at the level of synaptic inputs and spike outputs remains unclear along vertical cortical microcircuits. Here I compared subthreshold and suprathreshold sensitivity to prolonged monocular deprivation (MD) in rat binocular visual cortex in layer 4 and layer 2/3 pyramids (4Ps and 2/3Ps) and in thick-tufted and nontufted layer 5 pyramids (5TPs and 5NPs), which innervate different extracortical targets. In normal rats, 5TPs and 2/3Ps are the most binocular in terms of synaptic inputs, and 5NPs are the least. Spike responses of all 5TPs were highly binocular, whereas those of 2/3Ps were dominated by either the contralateral or ipsilateral eye. MD dramatically shifted the ocular preference of 2/3Ps and 4Ps, mostly by depressing deprived-eye inputs. Plasticity was profoundly different in layer 5. The subthreshold ocular preference shift was sevenfold smaller in 5TPs because of smaller depression of deprived inputs combined with a generalized loss of responsiveness, and was undetectable in 5NPs. Despite their modest ocular dominance change, spike responses of 5TPs consistently lost their typically high binocularity during MD. The comparison of MD effects on 2/3Ps and 5TPs, the main affected output cells of vertical microcircuits, indicated that subthreshold plasticity is not uniquely determined by the initial degree of input binocularity. The data raise the question of whether 5TPs are driven solely by 2/3Ps during MD. The different suprathreshold plasticity of the two cell populations could underlie distinct functional deficits in amblyopia.

When humans proactively manipulate objects, the applied fingertip forces primarily depend on feedforward, predictive neural control mechanisms that depend on internal representations of the physical properties of the objects. Here we investigate whether predictions of object properties also control fingertip forces that subjects generate reactively. We analyzed fingertip forces reactively supporting grasp stability in a restraining task that engaged two fingers. Each finger contacted a plate mounted on a separate torque motor, and, at unpredictable times, both plates were loaded simultaneously with forces tangential to the plates or just one of the plates was loaded. Thus, the apparatus acted as though the plates were mechanically linked or as though they were two independent objects. In different test series, each with a predominant behavior of the apparatus and with interspersed catch trials, we showed that the reactive responses clearly reflected the predominant behavior of the apparatus. Whether subject performed the task with one hand or bimanually, appropriate reactive fingertip forces developed when predominantly both contact plates were loaded or just one of the plates was loaded. When a finger was unexpectedly loaded during a catch trial, a weak initial reactive response was triggered, but the effective force development was delayed by approximately 100 msec. We conclude that the predicted physical properties of an object not only control fingertip forces during proactive but also in reactive manipulative tasks. Specifically, the automatic reactive responses reflect predictions at the level of individual digits as to the mechanical linkage of items contacted by the fingertips in manipulation.

27.

Ohnishi, Hiroshi

et al.

Gunma University.

Murata, Takaaki

Gunma University, Gunma University Graduate School of Medicine.

Kusakari, Shinya

Gunma University.

Hayashi, Yuriko

Gunma University.

Takao, Keizo

Kyoto University Graduate School of Medicine, Fujita Health University.

Severe stress induces changes in neuronal function that are implicated in stress-related disorders such as depression. The molecular mechanisms underlying the response of the brain to stress remain primarily unknown, however. Signal regulatory protein alpha (SIRPalpha) is an Ig-superfamily protein that undergoes tyrosine phosphorylation and binds the protein tyrosine phosphatase Shp2. Here we show that mice expressing a form of SIRPalpha that lacks most of the cytoplasmic region manifest prolonged immobility (depression-like behavior) in the forced swim (FS) test. FS stress induced marked tyrosine phosphorylation of SIRPalpha in the brain of wild-type mice through activation of Src family kinases. The SIRPalpha ligand CD47 was important for such SIRPalpha phosphorylation, and CD47-deficient mice also manifested prolonged immobility in the FS test. Moreover, FS stress-induced tyrosine phosphorylation of both the NR2B subunit of the NMDA subtype of glutamate receptor and the K+-channel subunit Kvbeta2 was regulated by SIRPalpha. Thus, tyrosine phosphorylation of SIRPalpha is important for regulation of depression-like behavior in the response of the brain to stress.

Many human studies have demonstrated that rapid motor responses (i.e., muscle-stretch reflexes) to mechanical perturbations can be modified by a participant's intended response. Here, we used a novel experimental paradigm to investigate the neural mechanisms that underlie such goal-dependent modulation. Two monkeys positioned their hand in a central area against a constant load and responded to mechanical perturbations by quickly placing their hand into visually defined spatial targets. The perturbation was chosen to excite a particular proximal arm muscle or isolated neuron in primary motor cortex and two targets were placed so that the hand was pushed away from one target (OUT target) and toward the other (IN target). We chose these targets because they produced behavioral responses analogous to the classical verbal instructions used in human studies. A third centrally located target was used to examine responses with a constant goal. Arm muscles and neurons robustly responded to the perturbation and showed clear goal-dependent responses ∼35 and 70 ms after perturbation onset, respectively. Most M1 neurons and all muscles displayed larger perturbation-related responses for the OUT target than the IN target. However, a substantial number of M1 neurons showed more complex patterns of target-dependent modulation not seen in muscles, including greater activity for the IN target than the OUT target, and changes in target preference over time. Together, our results reveal complex goal-dependent modulation of fast feedback responses in M1 that are present early enough to account for goal-dependent stretch responses in arm muscles.

Some elderly appear to resist age-related decline in cognitive functions, but the neural correlates of successful cognitive aging are not well known. Here, older human participants from a longitudinal study were classified as successful or average relative to the mean attrition-corrected cognitive development across 15-20 years in a population-based sample (n = 1561). Fifty-one successful elderly and 51 age-matched average elderly (mean age: 68.8 years) underwent functional magnetic resonance imaging while performing an episodic memory face-name paired-associates task. Successful older participants had higher BOLD signal during encoding than average participants, notably in the bilateral PFC and the left hippocampus (HC). The HC activation of the average, but not the successful, older group was lower than that of a young reference group (n = 45, mean age: 35.3 years). HC activation was correlated with task performance, thus likely contributing to the superior memory performance of successful older participants. The frontal BOLD response pattern might reflect individual differences present from young age. Additional analyses confirmed that both the initial cognitive level and the slope of cognitive change across the longitudinal measurement period contributed to the observed group differences in BOLD signal. Further, the differences between the older groups could not be accounted for by differences in brain structure. The current results suggest that one mechanism behind successful cognitive aging might be preservation of HC function combined with a high frontal responsivity. These findings highlight sources for heterogeneity in cognitive aging and may hold useful information for cognitive intervention studies.

We assess the relationship of age-related losses in striatal D1 receptor densities to age-related reductions in functional connectivity between spatially distinct cortical regions in healthy human participants. Previous neuroimaging studies have reported age-related differences in functional connectivity of the frontoparietal working memory network and the default mode network during task performance. We used functional magnetic resonance imaging and seed-based connectivity (right dorsolateral and medial prefrontal cortex) to extend these findings: Anterior-posterior connectivity of both these functional networks was reduced in older (65-75 years, n = 18) compared with younger (20-30 years, n = 19) adults, whereas bilateral connectivity in prefrontal cortex was increased in older adults. Positron emission tomography with the D1 receptor ligand [(11)C]SCH23390 was used to assess caudate D1 receptor density in the same sample. Older adults showed significantly reduced caudate D1 receptor density compared to the younger adults. Of key interest, partial correlations showed that individual differences in caudate D1 receptor density were positively associated with individual differences in dorsolateral prefrontal connectivity to right parietal cortex (BA40) and negatively with medial prefrontal connectivity to right parietal cortex (BA40 and postcentral gyrus), after controlling for age. We found no correlation of caudate D1 receptor density with anterior-posterior coupling within the default mode network or with bilateral frontal connectivity. These results are consistent with animal work that has identified a role for caudate D1 receptors in mediating information transfer between prefrontal areas and parietal cortex.

Increased frontal bilaterality in old compared with young adults during cognitive performance is a common finding in human functional neuroimaging studies. Age-related reductions in laterality are a widely debated topic and their origins and consequences may be manifold. The current study demonstrates that a dopamine (DA) D1 antagonist induces increased frontal bilateral connectivity in healthy young adults revealed by functional magnetic resonance imaging during a spatial working memory task. Moreover, increases in functional connectivity between right and left prefrontal cortex during the pharmacological challenge were associated with maintaining performance on drug. To our knowledge, this is the first study to pharmacologically induce increased frontal bilateral functional connectivity during a cognitive task in young adults and to show that increased bilaterality is associated with less severe cognitive impairment under the influence of a DA receptor antagonist.

The importance of face memory in humans and primates is well established, but little is known about the neurotransmitter systems involved in face recognition. We tested the hypothesis that face recognition is linked to dopamine (DA) activity in fusiform gyrus (FFG). DA availability was assessed by measuring D1 binding potential (BP) during rest using PET. We further assessed blood-oxygen-level-dependent (BOLD) signal change while subjects performed a face-recognition task during fMRI scanning. There was a strong association between D1 BP and BOLD activity in FFG, whereas D1 BP in striatal and other extrastriatal regions were unrelated to neural activity in FFG. These results suggest that D1 BP locally modulates FFG function during face recognition. Observed relationships among D1 BP, BOLD activity, and face-recognition performance further suggest that D1 receptors place constraints on the responsiveness of FFG neurons.

SIGNIFICANCE STATEMENT: The importance of face memory in humans and primates is well established, but little is known about the neurotransmitter systems involved in face recognition. Our work shows a role for a specific neurotransmitter system in face memory.

Although information in tactile afferent neurons represented by firing rates has been studied extensively over nearly a century, recent studies suggest that precise spike timing might be more important than firing rates. Here, we used information theory to compare the information content in the discharges of 92 tactile afferents distributed over the entire terminal segment of the fingertip when it was contacted by surfaces with different curvatures and force directions representative of everyday manipulations. Estimates of the information content with regard to curvature and force direction based on the precise timing of spikes were at least 2.2 times and 1.6 times, respectively, larger than that of spike counts during a 125 ms period of force increase. Moreover, the information regarding force direction based on the timing of the very first elicited spike was comparable with that provided by spike counts and more than twice as large with respect to object shape. For all encoding schemes, afferents terminating close to the stimulation site tended to convey more information about surface curvature than more remote afferents that tended to convey more information about force direction. Finally, coding schemes based on spike timing and spike counts overall contributed mostly independent information. We conclude that information about tactile stimuli in timing of spikes in primary afferents, even if limited to the first spikes, surpasses that contained in firing rates and that these measures of afferents' responses might capture different aspects of the stimulus.

Episodic memory declines with advancing age. Neuroimaging studies have associated such decline to age-related changes in general cognitive-control networks as well as to changes in process-specific encoding or retrieval networks. To assess the specific influence of aging on encoding and retrieval processes and associated brain systems, it is vital to dissociate encoding and retrieval from each other and from shared cognitive-control processes. We used multivariate partial-least-squares to analyze functional magnetic resonance imaging data from a large population-based sample (n = 292, 25-80 years). The participants performed a face-name paired-associates task and an active baseline task. The analysis revealed two significant network patterns. The first reflected a process-general encoding-retrieval network that included frontoparietal cortices and posterior hippocampus. The second pattern dissociated encoding and retrieval networks. The anterior hippocampus was differentially engaged during encoding. Brain scores, representing whole-brain integrated measures of how strongly an individual recruited a brain network, were correlated with cognitive performance and chronological age. The scores from the general cognitive-control network correlated negatively with episodic memory performance and positively with age. The encoding brain scores, which strongly reflected hippocampal functioning, correlated positively with episodic memory performance and negatively with age. Univariate analyses confirmed that bilateral hippocampus showed the most pronounced activity reduction in older age, and brain structure analyses found that the activity reduction partly related to hippocampus atrophy. Collectively, these findings suggest that age-related structural brain changes underlie age-related reductions in the efficient recruitment of a process-specific encoding network, which cascades into upregulated recruitment of a general cognitive-control network.

We continuously encounter and process novel events in the surrounding world, but only some episodes will leave detailed memory traces that can be recollected after weeks and months. Here, our aim was to monitor brain activity during encoding of events that eventually transforms into long-term stable memories. Previous functional magnetic resonance imaging (fMRI) studies have shown that the degree of activation of different brain regions during encoding is predictive of later recollection success. However, most of these studies tested participants' memories the same day as encoding occurred, whereas several lines of research suggest that extended post-encoding processing is of crucial importance for long-term consolidation. Using fMRI, we tested whether the same encoding mechanisms are predictive of recollection success after hours as after a retention interval of several weeks. Seventy-eight participants were scanned during an associative encoding task and given a source memory test the same day or after similar to 6 weeks. We found a strong link between regional activity levels during encoding and recollection success over short time intervals. However, results further showed that durable source memories, i.e., events recollected after several weeks, were not simply the events associated with the highest activity levels at encoding. Rather, strong levels of connectivity between the right hippocampus and perceptual areas, as well as with parts of the self-referential default-mode network, seemed instrumental in establishing durable source memories. Thus, we argue that an initial intensity-based encoding is necessary for short-term encoding of events, whereas additional processes involving hippocampal-cortical communication aid transformation into stable long-term memories.

In bimanual object manipulation tasks, people flexibly assign one hand as a prime actor while the other assists. Little is known, however, about the neural mechanisms deciding the role assignment. We addressed this issue in a task in which participants moved a cursor to hit targets on a screen by applying precisely coupled symmetrical opposing linear and twist forces on a tool held freely between the hands. In trials presented in an unpredictable order, the action of either the left or the right hand was spatially congruent with the cursor movements, which automatically rendered the left or right hand the dominant actor, respectively. Functional magnetic resonance imaging indicated that the hand-selection process engaged prefrontal cortical areas belonging to an executive control network presumed critical for judgment and decision-making and to a salience network attributed to evaluation of utility of actions. Task initiation, which involved switching between task sets, had a superordinate role with reference to hand selection. Behavioral and brain imaging data indicated that participants initially expressed two competing action representations, matching either mapping rule, before selecting the appropriate one based on the consequences of the initial manual actions. We conclude that implicit processes engaging the prefrontal cortex reconcile selections among action representations that compete for the establishment of a dominant actor in bimanual object manipulation tasks. The representation selected is the one that optimizes performance by relying on the superior capacity of the brain to process spatial congruent, as opposed to noncongruent, mappings between manual actions and desired movement goals.

Progesterone, or rather its neuroactive metabolite allopregnanolone, modulates amygdala activity and thereby influences anxiety. Cognition and, in particular, memory are also altered by allopregnanolone. In the present study, we investigated whether allopregnanolone modulates memory for biologically salient stimuli by influencing amygdala activity, which in turn may affect neural processes in other brain regions. A single progesterone dose was administered orally to healthy young women in a double-blind, placebo-controlled, crossover design, and participants were asked to memorize and recognize faces while undergoing functional magnetic resonance imaging. Progesterone decreased recognition accuracy without affecting reaction times. The imaging results show that the amygdala, hippocampus, and fusiform gyrus supported memory formation. Importantly, progesterone decreased responses to faces in the amygdala and fusiform gyrus during memory encoding, whereas it increased hippocampal responses. The progesterone-induced decrease in neural activity in the amygdala and fusiform gyrus predicted the decrease in memory performance across subjects. However, progesterone did not modulate the differential activation between subsequently remembered and subsequently forgotten faces in these areas. A similar pattern of results was observed in the fusiform gyrus and prefrontal cortex during memory retrieval. These results suggest that allopregnanolone impairs memory by reducing the recruitment of those brain regions that support memory formation and retrieval. Given the important role of the amygdala in the modulation of memory, these results suggest that allopregnanolone alters memory by influencing amygdala activity, which in turn may affect memory processes in other brain regions.

Endogenous neurosteroids have rapid actions on ion channels, particularly GABA(A) receptors, which are potentiated by nanomolar concentrations of 3alpha-hydroxypregnane neurosteroids. Previous evidence suggests that 3beta-hydroxypregnane steroids may competitively antagonize potentiation induced by their 3alpha diastereomers. Because of the potential importance of antagonists as experimental and clinical tools, we characterized the functional effect of 3beta-hydroxysteroids. Although 3beta-hydroxysteroids reduced the potentiation induced by 3alpha-hydroxysteroids, 3beta-hydroxysteroids acted noncompetitively with respect to potentiating steroids and inhibited the largest degrees of potentiation most effectively. Potentiation by high concentrations of barbiturates was also reduced by 3beta-hydroxysteroids. 3beta-Hydroxysteroids are also direct, noncompetitive GABA(A) receptor antagonists. 3beta-Hydroxysteroids coapplied with GABA significantly inhibited responses to > or =15 microm GABA. The profile of block was similar to that exhibited by sulfated steroids, known blockers of GABA(A) receptors. This direct, noncompetitive effect of 3beta-hydroxysteroids was sufficient to account for the apparent antagonism of potentiating steroids. Mutated receptors exhibiting decreased sensitivity to sulfated steroid block were insensitive to both the direct effects of 3beta-hydroxysteroids on GABA(A) responses and the reduction of potentiating steroid effects. At concentrations that had little effect on GABAergic synaptic currents, 3beta-hydroxysteroids and low concentrations of sulfated steroids significantly reversed the potentiation of synaptic currents induced by 3alpha-hydroxysteroids. We conclude that 3beta-hydroxypregnane steroids are not direct antagonists of potentiating steroids but rather are noncompetitive, likely state-dependent, blockers of GABA(A) receptors. Nevertheless, these steroids may be useful functional blockers of potentiating steroids when used at concentrations that do not affect baseline neurotransmission.